rs137853176

Variant names:

• chr4-153703172-A-G
• rs137853176
• NM_001318789.2:c.265A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001318789.2(TLR2):​c.265A>G​(p.Asn89Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: TLR2 NM_001318789.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -1.79
• Publications: 6 publications found

Genes affected

TLR2 (HGNC:11848): (toll like receptor 2) The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. This protein is a cell-surface protein that can form heterodimers with other TLR family members to recognize conserved molecules derived from microorganisms known as pathogen-associated molecular patterns (PAMPs). Activation of TLRs by PAMPs leads to an up-regulation of signaling pathways to modulate the host's inflammatory response. This gene is also thought to promote apoptosis in response to bacterial lipoproteins. This gene has been implicated in the pathogenesis of several autoimmune diseases. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.069251746).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318789.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR2	NM_001318789.2	MANE Select	c.265A>G	p.Asn89Asp	missense	Exon 3 of 3	NP_001305718.1	O60603
	TLR2	NM_001318787.2		c.265A>G	p.Asn89Asp	missense	Exon 4 of 4	NP_001305716.1	A0A0S2Z4S4
	TLR2	NM_001318790.2		c.265A>G	p.Asn89Asp	missense	Exon 3 of 3	NP_001305719.1	A0A0S2Z4S4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR2	ENST00000642700.2	MANE Select	c.265A>G	p.Asn89Asp	missense	Exon 3 of 3	ENSP00000494425.1	O60603
	TLR2	ENST00000260010.7	TSL:6	c.265A>G	p.Asn89Asp	missense	Exon 3 of 3	ENSP00000260010.6	O60603
	TLR2	ENST00000642580.1		c.265A>G	p.Asn89Asp	missense	Exon 3 of 3	ENSP00000495339.1	O60603

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251260 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.26
DANN	Benign	0.55
DEOGEN2	Benign	0.098	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.59	N
PhyloP100		-1.8
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.17
Sift	Benign	0.64	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.051
MutPred		0.24		Gain of disorder (P = 0.1574)
MVP		0.60
MPC		0.074
ClinPred		0.038	T
GERP RS		-9.7
PromoterAI		0.0062	Neutral
Varity_R		0.30
gMVP		0.26
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137853176; hg19: chr4-154624324;